(4&#39;-(phenyl-3 6-dihydro-1-(2h)-pyridyl)-2-hydroxy propoxy-anilides and derivatives thereof

ABSTRACT

Substituted (3-(4-phenyl-1-hydropyridyl)-propoxy or propylthio)anilines prepared, inter alia, by reacting the correspondingly substituted propoxy or propyl-thio anilines and N-phenyl-hydropyridines, are described. The end products, i.e., the substituted (3-(4-phenyl-1-hydropyridyl)-propoxy or propylthio)anilines are useful as antiphlogistic, antiallergic, antitussive and analgesic agents.

United States Patent Edenhofer et al.

[ 1 July4, 1972 [54] [4'-(PllENYL-3,6-DIHYDRO-l-(2H)- PYRIDYLl-Z-HYDROXY PROPOXY- ANILIDES AND DERIVATIVES THEREOF [72] Inventors: Albrecht Edenhofer, Riehen; Hans Spiegelberg, Basel, both of Switzerland [73] Assignee: Hoffmann-La Roche Inc., Nutley, NJ.

[22] Filed: Dec. 4, 1969 [21 Appl. No.: 882,298

[30] Foreign Application Priority Data Dec. 24, 1968 Switzerland ..l9268/68 [52] US. Cl ..260/294.8 F, 260/294.8 G, 260/295 R,

260/295 AM, 260/295 S, 260/296 R, 260/297 R, 260/293.72, 260/293.73, 260/2938, 260/293.8l, 260/293.82, 424/263, 424/266, 424/267 [51] Int. Cl. ..C07d 31/50 [58] Field of Search ..260/295 AM [56] References Cited UNITED STATES PATENTS 3,515,788 6/1970 Edenhofer et al ..260/297 R Primary Examiner-Alan L. Rotman Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S. Leon and William G. lsgro s7 ABSTRACT 15 Claims, N0 Drawings [4'-(PIIENYL-3 ,6-DIHYDRO-l-(2ID-PYRIDYL1-2- I-IYDROXY PROPOXY-ANILIDES AND DERIVATIVES THEREOF BRIEF SUMMARY OF THE INVENTION The invention relates to aromatic ethers of the formula Q-x-cm-w-om-w IIb wherein R" is lower alkanoylamido of three to seven carbon atoms, carbamoyl or ureido; R' is hydrogen or halogen; X is oxy or thio; Y' is methylene or hydroxymethylene; and Z' is halogen or taken together with Y and the end methylene group is DETAILED DESCRIPTION OF THE INVENTION The invention relates to aromatic ethers of the formula wherein R is hydrogen, amino, mono-(lower alkyl) amino, lower alkanoylamido, aroylamido, N-(lower alkyl) lower alkanoylamido, lower alkylsulfonylamido, carbamoyl or ureido; R is hydrogen, halogen, lower alltyl or lower alkoxy; R is halogen; R, is hydrogen; R, is hydrogen or hydroxy; R, together with R; is a carbon to carbon bond; X is oxy or thio; and Y is methylene, hydroxymethylene, lower alkanoyloxymethylene, lower alkylsulfonyloxymethylene, arylsulfonyloxymethylene or carbonyl, and their pharmaceutically acceptable acid addition salts.

As used herein, the term lower alkyl denotes straight or branched chain lower alkyl of one to six carbon atoms, for example, methyl, ethyl, isopropyl, butyl, pentyl and the like. The term lower alkoxy denotes lower alkyl ether groups in which the lower alkyl is as described above, for example,

methoxy, ethoxy, isopropoxy and the like. The term halogen denotes chlorine, bromine,'fluorine and iodine. Of the halogen atoms, fluorine and chlorine are preferred.

The amino group can be substituted by lower alkyl of one to six carbon atoms, such as, for example, methyl-, ethyl-, propyl-, butylor pentyl-amino and the like. The term lower alkanoyl" denotes a residue of a carboxylic acid of one to six carbon atoms, for example, formyl, acetyl, propionyl or the like; acetyl is preferred. The term aroy denotes a residue of a halogen substituted aromatic carboxylic acid with up to ll carbon atoms, for example, p-chlorobenzoyl and the like. The

lower alkyl-sulfonyl residues are derived from sulfuric acid substituted by lower alkyl, for example, methylsulfonyl, ethylsulfonyl and the like; methylsulfonyl is preferred. The term aryl" denotes phenyl or phenyl bearing'a lower alkyl one to four carbon atoms; of these, p-tolyl is preferred.

The carbamoyl group can be monoor di-substituted by lower alkyl of one to six carbon atoms or mono-substituted by phenyl or halo-substituted phenyl, such as for example, the N- methylcarbamoyl, N,N-dimethylcarbamoyl, N-isopropylcarbamoyl, N-isobutylcarbamoyl, N-tert. butylcarbamoyl, N- phenylcarbamoyl and the like.

The ureido group can also be substituted by lower alkyl of one to six carbon atoms, for example, methylureido, isopropylureido and the like.

Representative examples of the compounds of formula I are:

rac-p- {3-[4-(p-fluoro-phenyl)-3,6-dihydrol (2H)-pyridyl]- Z-hydroxy-propoxykaniline:

rac-o- {3-[4-(p-fluoro-phenyD-3 ,o-dihydrol 2H)-pyridyl 2-hydroxy-propoxy}-N-methylaniline;

rac-4' 3-[4-(p-chloro-phenyl)-3 ,6-dihydro 1 (2H pyridyl1-2-hydroxy-propoxy}-acetanilide;

rac-4'-[{3-[4-(p-fluoro-phenyll-3 ,6-dihydro- 1 (2H pyridyl]-2-hydroxy-propyl} -thi0] -acetanilide;

rac-4'-{3-[4-(p-fluoro-phenyl )-3,6-dihydro- 1 (2H pyridyl]-2-hydroxy-propoxy}-propionanilide;

rac-4 3-[4-(p-fluoro-phenyl)-3 .6-dihydro- 1 (2H pyridyl]-2-hydroxy-propyl}-thiol-methanesulfonanilide;

rac-4-{3-[4-(p-chloro-phenyl)-4-hydroxy-piperidino]-2- hydroxy-propoxy}-acetanilide;

4'- 3-l4-(p-fluoro-phenyl)-3,6-dihydro-l(2I-I)-pyridyl]- propyl}-thiol-methanesulfonanilide;

rac-p-[{3-l4-(p-fluoro-phenyD-3.6-dihydro-l(2H- pyridyll-2-hydroxy-propyll-thio] anisole, and the like.

In naming the compounds of fonnula I, the group when present, can be identified either as a 3-( Il -phenyl)- l,2,3,6-tetrahydro-l-pyridyl group or as a 4-(R;,-phenyl)-3,6- dihydro-l-( 2I-I)pyridyl group. The latter nomenclature is employed herein.

The compounds of the invention can be prepared by the following processes:

a. A compound of the formula R2 II wherein R X and Y are as previously described; R, is hydrogen, nitro, lower alkanoylamido, N-(lower alkyl) lower alkanoylamido, aroylamido, carbamoyl or ureido; Z is halogen, lower alkyl-sulfonyloxy, arylsulfonyloxy, or when taken together with Y and the end methylene group is is reacted with a compound of the formula wherein R',, R and X are as previously described is reacted with a compound of the formula wherein R R,, R, X and Z are as previously described.

The product obtained in a given case can be further modified. For example, a nitro group is reduced; a 3,6- dihydro-l(2l-l)-pyridyl residue is hydrogenated, if desired; an acylamido group is saponified, if desired; an amino group is acylated or alkylated, if desired; a carbonyl group is reduced to the hydroxymethylene or methylene group, if desired; and the compound of formula I thus obtained is optionally converted into a pharrnaceutically acceptable acid addition salt.

The starting compounds of formula II in part are new compounds. 4-(2,3-Epoxy-propoxy)-propionanilide, for example, is a new compound which, for instance, can be prepared by reacting excess epihalohydrin with p-hydroxy-propionanilide in the presence of an excess of aqueous caustic alkali, preferably caustic soda, conveniently at room temperature.

The corresponding 4'-[2-hydroxy-3-haIo-propoxy]- propionanilide can, for example, be prepared by reacting an acid addition salt of a tertiary base such as pyridine hydrochloride or triethylamine hydrochloride, with the epoxide named hereinbefore in a protic solvent such as a lower alkanol, for example methanol and the like, preferably at a temperature in the range of between about room temperature and the boiling point of the reaction mixture. The corresponding 4'-[2-hydroxy-3-tosyloxy-propoxy]-propionanilide can be prepared from the epoxide and p-toluenesulfonic acid as described hereinbefore. The other compounds of formula ll can be prepared in an analogous manner. The new compounds are characterized by the formula wherein R", is lower alkanoylamido of three to seven atoms, carbamoyl or ureido; R' is hydrogen or halogen; X is oxy or thio; Y is methylene or hydroxymethylene; and Z is halogen or taken together with Y and the end methylene group is The reactants of formula Ill, for example, p-fluorophenyll,2,3,6-tetrahydropyridine and the like, are generally known compounds or can be prepared in accordance with known procedures.

The reaction of the compounds of formula II with compounds of formula lll is advantageously carried out so that the corresponding epoxide of a compound of formula ll is reacted with the compound of formula III in a polar organic solvent, for example, in a lower alkanol, such as methanol and the like, or in a cyclic ether such as dioxane, at a temperature in the range of between about room temperature and the boiling temperature of the reaction mixture, or so that the corresponding halo or tosyloxy compound of formula ll is reacted with a compound of fonnula III in the presence of potassium or sodium carbonate in a lower alkanol such as ethanol or isopropanol, or in dimethylformamide or tetrahydrofuran at a temperature in the range of between about room temperature and the boiling temperature of the reaction mixture.

The starting compounds of formula IV, for example phydroxy-propionanilide, are generally known compounds orcan be prepared in accordance with known procedures.

The reactants of formula V are known compounds.

If an acid binding agent, e.g., an aqueous or an alkanolic alkali metal hydroxide solution, particularly an aqueous potassium hydroxide solution or an ethanolic potassium hydroxide solution, is allowed to act on a halohydrine compound, preferably at room temperature, a corresponding epoxide of formula V is obtained.

The corresponding tosyloxy compound of formula V can be prepared by reacting the epoxide obtained with p-toluene-sulfonic acid. The other compounds of formula V can be prepared in an analogous manner.

The reaction of the compounds of formula IV with halo or tosyl compounds of formula V is advantageously carried out in such a way that the two reaction components are allowed to react with each other in the presence of an alkali alkanolate, conveniently at the boiling temperature of the reaction mixture.

If an epoxide of a compound of formula V is utilized, the reaction with a compound of formula IV is preferably carried out in the presence of a catalytic amount of an organic or inorganic base, for example pyridine or potassium hydroxide, in a polar solvent, preferably a lower alkanol such as ethanol, or in a cyclic ether such as dioxane, conveniently at the boiling temperature of the reaction mixture.

The compounds of formula I with a 3,6-dihydro-l(2l-l)- pyridyl residue can be hydrogenated. In this case, the pyridyl compound is converted into the corresponding piperidine compound in the presence of a noble metal catalyst, preferably in an organic solvent, for example, an alkanol such as methanol or ethanol. The hydrogenation can be carried out under normal or super atmospheric pressure, at room temperature or at a temperature in the range of between about room temperature and the boiling point of the reaction mixture.

The compounds obtained which contain a nitro group are reduced in a known manner, conveniently in a chemical or catalytic manner, for example, with tin/hydrochloric acid or with hydrogen in the presence of a noble metal catalyst. The hydrogenation is preferably carried out under normal pressure at room temperature in the presence of an alkanol, preferably in ethanol, in the presence of palladium/charcoal or platinum oxide as the catalyst.

The compounds of formula I wherein R is an acylamido group can be saponified in a known manner with acidic or alkaline agents, for example, dilute aqueous alkali or aqueous acid. The saponification is advantageously carried out with a 20 percent aqueous hydrochloric acid at elevated temperature, preferably at the boiling temperature of the reaction mixture.

The compounds of formula I wherein R is an amino group can be N-acylated in a known manner, for example, by treatment with an acid halide or acid anhydride. When employing alkanoyl, aroyl or alkylsulfonyl halides, the N-acylation is expediently carried out in the presence of a base, for example, pyridine or triethylamine, in the cold, preferably at a temperature in the range of about 0 to about 5 C. When employing alkanoyl or aroyl anhydrides, it can be carried out in the presence of a protic solvent, for example, a lower alkanol,

such as methanol or ethanol, as well as in the presence of dilute acetic acid, preferably at room temperature.

The compounds of formula I wherein R is an amino or acylamido group can be N-alkylated in a known manner, for example, with alkyl halides. Under such circumstances, conveniently the corresponding compound is immediately reacted with the alkyl halide in the presence of sodium hydride at a temperature in the range of between about and room temperature.

The compounds of formula I wherein R is an amino group can be methylated with the aid of formaldehyde/formic acid. More particularly, the amine is dissolved in 90 percent formic acid and treated with 40 percent formaldehyde. Before working up, the reaction mixture is conveniently heated further on the steam bath for an extended period of time after cessation of the evolution of carbon dioxide.

The compounds of formula I wherein Y is a carbonyl group can be reduced to compounds of formula I wherein Y is a hydroxymethylene group in a known manner, for example, by treatment with a complex metal hydride, preferably a complex borohydride. The reduction is expediently carried out with the aid of an alkali metal borohydride, preferably sodium borohydride, in a lower alkanol such as ethanol, at a temperature in the range of between about room temperature and the boiling temperature of the reaction mixture.

The compounds of formula I wherein Y is a hydroxymethylene group can be acylated in a known manner, for example, by reacting with an alkanoyl-, alkylsulfonylor an arylsulfonyl halide conveniently in the presence of a base such as pyridine or triethylamine or by reacting with corresponding anhydride, for example, acetic anhydride. The acylation can be carried out at a temperature in the range of between about room temperature and the boiling temperature of the reaction mixture, also in the presence of aprotic polar solvents such as dimethylsulfoxide. An amine group which may be present will also acylate under these conditions.

The compounds of formula I wherein Y is hydroxymethylene and/or R is hydroxy are obtained as racemates. These can be separated into the optical antipodes in a known manner, for example, with the aid of optically active acids such as tartaric acid. The separation of the antipodes can also be carried out on the intermediate compounds when R is nitro.

The compounds of formula I form acid addition salts with inorganic or organic acids. Exemplary of these are: salts with hydrohalic acids such as hydrochloric or hydrobromic acid, salts with mineral acids, for example with sulfuric acid, or also salts with organic acids, for example, with benzoic acid, acetic acid, tartaric acid, citric acid, lactic acid and the like.

The aromatic ethers of formula I prepared in accordance with the invention have antiphlogistic, antiallergic, antitussive and analgesic activity and are useful as antiphlogistic antiallergic, antitussive and analgesic agents. Compounds of formula I wherein R is acylamino; R is hydrogen; R is fluorine or chloride; X is oxy or thio and Y is hydroxymethylene are preferred compounds. Rae-4-{3-[4-(p-fluoro-phenyl)- 3,6-dihydro-1(2H)-pyridy|]-2-hydroxy-propoxy}-isobutyranilide exhibits particularly strong activity. The toxicity of this compound is low. In rats, on oral administration, the lethal dosage [LD is about 750 mg/kg. The anti-inflammatory activity has been demonstrated in rats at a dosage of 30 mg. p.o./kg.

The aromatic ethers of formula I can accordingly be used, for example, for combatting rheumatic diseases. For such uses, up to about I00 mg. per day of the compounds of formula I, as exemplified by rac-4'-{3-[4(p-fluoro-phenyl)-3,6- dihydro- 1 (2H )-pyridyl1-2-hydroxy-propoxy}-isobutyranilide can be administered in divided doses.

The antitussive, analgesic and antiallergic activities can also be demonstrated in animals in accordance with standard procedures. Rae-4-{3-[4-(p-tluoro-phenyl)-3,6-dihydro- 1 (2H )-pyridyl -2-hydroxy-propoxy}-isobutyranilidc, when administered orally to Guinea pigs at a dose of mg/kg., exhibits antitussive activity.

Rac-4- {3-[4-( p-fluorophenyl)-3 ,6-dihydro-l (2H)- pyridyl]--2-hydroxy-propoxy}-propionanilide, when administered orally to rats at a dose of 30 mg/kg., exhibits analgesic activity.

4'- {3-[ 4-( p-fluoro-phenyl )-3,6-dihydrol (2I-I)-pyridyl]- propoxy}-acetanilide, when administered orally to Guinea pigs at a dose of 3 mg/kg., exhibits antiallergic activity.

The compounds of formula I can be used in the form of pharmaceutical preparations which contain them or their salts in admixture with an organic or inorganic pharmaceutically inert carrier suitable for enteral or parenteral application such as, for example, water, gelatin, gum arabic, lactose, starches, vegetable oils, polyalkyleneglycols, and the like. The pharmaceutical preparations can be in solid form, for example, tablets, dragees, suppositories or capsules, or in liquid form, for example, as solutions, suspensions or emulsions. The preparation may be sterilized and/or contain additives, such as preservatives, stabilizers, wetting or emulsifying agents, or salts for varying the osmotic pressure. The pharmaceutical preparations can also contain additional therapeutically active substances.

EXAMPLE 1 Preparation of rac-2'-{3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2H)-pyridyl]-2-hydroxy-propoxy}-acetanilide 4.1 g. of 2'- (2,3-epoxy-propoxy)-acetanilide and 3.8 g. of 4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine are heated under reflux conditions in 30 ml. of ethanol for l hour. The solvent is removed by evaporation under reduced pressure. The residual oily rac-2'- {3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1 (2H pyridyl]-2-hydroxy-propoxy}acetanilide is dissolved in ethyl acetate and treated with alcoholic hydrochloric acid to a congo-acidic reaction. The hydrochloride salt of rac.-2-{3- [4-( p-fluoro-phenyl )-3 ,6-dihydrol 2l-I)-pyridyl ]-2-hydroxypropoxy}-acetanilide melts at 237238 C. after recrystallization from ethanol.

In analogous manner there is obtained:

By the reaction of 4-(2,3-epoxy-propoxy)-acetanilide and 4-(p-chloro-phenyl)-l ,2,3,6-tetrahydropyridine: rac-4'-{ 3-[4-( p-chloro-phenyl)-3 ,6-dihydr0- l 2H )-pyridyl]-2- hydroxy-propoxy}-acetanilide, having a melting point of l-l 86 C. (from ethanol);

By the reaction of 2'-(2,3-epoxy-propoxy)-acetanilide and 4-(p-chloro-phenyl)- l ,2,3,6-tetrahydropyridine: rac-2 3-[4-( p-chloro-phenyl)-3 ,6-dihydro- 1 (2H )-pyridyl]-2- hydroxy-propoxy}-acetanilide hydrochloride, having a melting point of l36l37 C. (dec.) (from methanol/ethyl acetate);

By the reaction of 2-(2,3-epoxy-propoxy)-acetanilide and 4-(p-fluoro-phenyl)-4-hydroxy-piperidine: rac-2 {3 4- (p-fluoro-phenyl)-4-hydroxy-piperidino]-2-hydroxypropoxy}-acetanilide hydrochloride, having a melting point of 2 l 9-220 C. (from ethanol/ether);

By the reaction of 2'-(2,3-epoxy-propoxy)-acetanilide and 4-(p-fluoro-phenyl)- l ,2,3 ,-tetrahydropyridine: rac-2'-{ 3-[4-(p-fluoro-phenyl )-3 ,6-dihydro- 1 (2H )-pyridyl]-2- hydroxy-propoxy}-acetanilide hydrochloride, having a melting point of 20l202 C. (from ethanol/ethyl acetate);

By the reaction of 2'-(2,3-epoxy-propoxy)-acetanilide and 4-(p-fluoro-phenyl)-piperidine: rac-2-{3[4-(p-fluorophenyl)-piperidino]-hydroxy-propoxy} -acetanilide hydrochloride, having a melting point of l33-l35 C.

. (from ethanol/ethyl acetate);

By the reaction of 5'-chloro-2'-(2,3-epoxy-propoxy)- acetanilide and 4-(p-fluoro-phenyl)- l ,2,3 ,6- tetrahydropyridine: rac-S '-chloro-2- {3-[ 4-(p-fluorophenyl)-3 ,6-dihydro- 1 (2H )-pyridyl]-2-hydroxy-propoxy} -acetanilide hydrochloride, having a melting point of -l 78 C. (from methanol/ethyl acetate).

The 5'-chloro-2'-(2,3-epoxy-propoxy)-acetanilide ployed above can be prepared as follows:

37.1 g. of 4-chloro-Z-acetamino-phenol are introduced into a solution containing 9.6 g. of sodium hydroxide in 200 ml. of water and, following the addition of 92.5 g. of epichlorohydrin, the mixture is intensively stirred at room temperature for 20 hours. After washing with water, the precipitate which forms is recrystallized from ethyl acetate/petroleum ether to yield '-chloro-2-(2,3-epoxypropoxy)-acetanilide, which melts at 87-88 C.

By the reaction of 3'-(2,3-epoxy-propoxy)-acetanilide and 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine: rac-3-{ 3-[4-(p-fluoro-phenyl)-3,6-dihydro-l (2H)-pyridyl]-2- hydroxy-propoxy}-acetanilide hydrochloride, having a melting point of about 125 C. (from ethanol/ethyl acetate).

The 3'-(2,3-epoxy-propoxy)-acetanilide employed above can be prepared as follows:

100 g. of 3-acetamino-phenyl are introduced into a solution containing 32 g. of sodium hydroxide in 660 ml. of water and the resulting mixture is treated at once with 306 g. of epichlorohydrin. The mixture is intensively stirred at room temperature for 16 hours and subsequently extracted with chloroform. The 3-(2,3-epoxy-propoxy)-acetanilide which remains after evaporation of the solvent from the organic phase melts at 70-7l C. after recrystallization from ethyl acetate/isopropyl ether.

By the reaction of 2'-(2,3-epoxy-propoxy)-propionanilide and 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine: rac- 2'-{3-[4-(p-fluoro-phenyl)-3,6-dihydro-1 (2l-l)-pyridyl]- 2-hydroxy-propoxy}-propionanilide having a melting point of 187l88 C. (from ethanol/ethyl acetate).

The 2'-(2,3-epoxy-propoxy)-propionanilide employed above can be prepared as follows:

87.5 g. of 2-propionamino-phenol are introduced into a solution containing 24 g. of sodium hydroxide in 500 ml. of water and the mixture is treated with 231.2 g. of epichlorohydrin. The mixture is intensively stirred at room temperature for hours. The oil which separates out is extracted with chloroform. The 2'-(2,3-epoxy-propoxyl)- propionanilide, which remains after evaporation of the solvent from the organic phase, melts at 74-75 C., after recrystallization from ethyl acetate/petroleum ether.

By the reaction of 4-(2,3-epoxy-propoxy)-acetanilide and 4-(p-chloro-phenyl)-4-hydroxy-piperidine; rac-4'-{3-[4- (p-chloro-phenyl)-4-hydroxy-piperidino]-2-hydroxypropoxy}-acetanilide hydrochloride having a melting point of 236 C. (dec.) (from ethyl acetate/ether);

By the reaction of 4-(2,3-epoxy-propoxy)-propionanilide 3-[4-(p-fluoro-phenyl)-3 ,6-dihydro- 1 (2H )-pyridyl]-2- hydroxy-propoxy}-propionanilide hydrochloride having a melting point of 21 l2l3 C. (from methanol/ethyl acetate).

The 4-(2,3-epoxy-propoxy)-propionanilide employed above can be prepared in an analogous manner as described above for 2-(2,3-epoxy-propoxy)-propionanilide and has a melting point of 1 l7l 20 C. (from ethyl acetate/petroleum ether).

By the reaction of 4'-(2,3-epoxy-propoxy)-butyr-anilide and 4-(p-fluoro-phenyl)- 1 ,2,3,G-tetrahydropyridine: rac- 4'- {3-[4-(p-fluoro-phenyl)-3,6-dihydrol 2H) pyridyl]- 2-hydroxy-propoxy}-butyranilide hydrochloride having a melting point of 206-208 C. (from methanol).

The 4'-(2,3-epoxy-propoxy)-butyranilide employed above can be prepared in an analogous manner as described above for 2'-(2,3-epoxy-propoxy)-propionanilde and has a melting point of l02l03 C. (from ethyl acetate/petroleum ether).

By the reaction of 4'-(2,3-epoxy-propoxy)-isobutyranilide and 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine: rac. 4- {3-[4-(p-fluoro-phenyl)-3,6-dihydro-1(2l-l)-pyridyl]- 2-hydroxy-propoxy }-isobutyranilide hydrochloride having a melting point of l80l 82 C. (from methanol).

The 4'-(2,3-epoxy-propoxy)-isobutyranilide employed above can be manufactured in an analogous manner as described above, having a melting point of l25-126 C. (from ethyl acetate/petroleum ether).

EXAMPLE 2 Preparation of rac-2'-{3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2H)-pyridyl ]-2-hydroxy-propoxy}-N-methyl-acetanilide 4.4 g. of 2'-(2,3-epoxy-propoxy)-N-metbyl-acetanilide and 3.6 g. of 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine are heated under reflux conditions in 50 ml. of ethanol for 1 hour. The oily rac-2-{3-[4-(p-fluoro-phenyl)-3,6-dihydro-l(2H)- pyridyl]-2-hydroxy-propoxy}-N-methyl-acetanilide which remains after evaporation of the solvent is chromatographed on a column of silica gel with ether and methanol as eluting agents. The conversion to the hydrochloride is effected in the usual manner by acidification of the solution in ethyl acetate with alcoholic hydrochloric acid up to the congo-acidic reaction. The rac-2"{3-[4-(p-fluoro-phenyl)-3,fi-dihydro-l(2H)- pyridyl]-2-hydroxy-propoxy}-N-methyl-acetanilide hydrochloride melts at l57-l 60 C.

The oily 2-(2,3-epoxy-propoxy)-N-methyl-acetanilide employed above can be prepared in an analogous manner as described in Example 1, n1 1.523.

EXAMPLE 3 Preparation of rac-p-{ 3-[ 4-( p-fluoro-phenyl )-3 ,6-dihydr0- l( 2H)-pyridyl ]-2-hydroxy-propoxy} -phenyl-urea 4.2 g. of [p-(2,3-epoxy-propoxy)-phenyl]-urea and 3.54 g. of 4-(p-fluoro-phenyl)-l ,2,3,6-tetrahydropyridine are heated under reflux conditions in 40 ml. of ethanol for 1 hour. The rac-p-{ 3-[4-(p-fluoro-phenyl)-3,6-dihydro-l (2H)-pyridyl]-2- hydroxy-propoxy}-phenyl-urea which separates out on cooling is removed by filtration under suction, dissolved in ethanol with slight warming and converted to the hydrochloride by addition of alcoholic hydrochloric acid up to a congo-acidic reaction. The rac-p- {3-[4-(p-fluoro-phenyl)-3.6-dihydrol( 2H)-pyridyl]-2-hydroxy-propoxy}-phenyl-urea hydrochloride melts at 241 C. (from water).

In an analogous manner there is obtained:

By the reaction of [o-(2,3-epoxy-propoxy)-phenyl]-urea and 4-(p-fluoro-phenyl)-l ,2,3,6-tetrahydropyridine: rac- [o-{3[4-(p-fluoro-phenyl)-3 ,6-dihydrol (2H)-pyridyl]-2- hydroxy-propoxy}-phenyll-urea hydrochloride having a melting point of 21 1-2 13 C. (from methanol/water).

The [o-( 2,3-epoxy-propoxy)-phenyll-urea employed above can be prepared in an analogous manner as described above. The oily compound obtained can be further processed without further purification.

EXAMPLE 4 Preparation of rac-4'- {3-[4-p-fluoro-phenyl)-3,6-dihydrol( 2H)-pyridyl]-2-hydroxy-propoxy} -benzanilide 5.4 g. of 4-(2,3-epoxy-propoxy)-benzanilide and 3.5 g. of 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine are heated under reflux conditions in 50 ml. of ethanol for 3 hours. The crystalline rac-4-{3-[4-(p-fluoro-phenyl )-3,6-dihydrol 2H)- pyridyl]-2-hydroxy-propoxy} -benzanilide obtained after cooling is converted in the usual manner to the hydrochloride, which melts at 222-224 C. after recrystallization from ethanol.

The 4'-(2,3-epoxy-propoxy)-benzanilide employed above can be prepared as follows:

42.8 g. of p-hydroxy-benzanilide are introduced to a solution containing 9.6 g. of sodium hydroxide in 200 ml. of water and treated with stirring with 92.6 g. of epichlorohydrin. The mixture is stirred at room temperature for 16 hours. The 4- (2,3-epoxy-propoxy)-benzanilide which separates out is washed with water, dissolved in chloroform and shaken with excess 3N caustic soda for 1 hour. The 4'-(2,3-epoxy-propoxy)-benzanilide isolated from the organic phase melts at l55- 1 56 C. after recrystallization from methanol.

EXAMPLE Preparation of rac. l-{3-[4-(p-fluoro-phenyl)-3,6-dihydrol 2H )-pyridyl]-2-hydroxy-propoxy}-benzamide 1.9 g. of o-(2,3-epoxy-propoxy)-benzamide and 1.8 g. of 4- (p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine are heated under reflux conditions in 20 ml. of ethanol for 1 hour. The rac. l- {3- 4-(p-fluoro-phenyl)-3 ,6-dihydrol 2H)-pyridyl]-2- hydroxy-propoxy}-benzamide which separates out upon cooling is converted 'to the hydrochloride by treatment with alcoholic hydrochloric acid. The hydrochloride salt melts at 19 l- 1 93 C. after recrystallization from ethanol/ether.

In an analogous manner there is obtained:

By the reaction of p-(2,3-epoxy-propoxy)-benzamide and 4- (p-fluoro-phenyl)- l ,2,3,6-tetrahydropyridine: rac.-p-{3-[ 4-( p-fluoro-phenyl )-3,6-dihydrol 2H )-pyridy1]-2- hydroxy-propoxy}-benzamide hydrochloride having a melting point of 267269 C.

The p-(2,3-epoxy-propoxy)-benzamide employed above can be prepared as follows:

4.1 g. of p-hydroxybenzamide are added to a solution containing 1.45 g. of sodium hydroxide in 30 ml. of water and treated with 14 g. of epichlorohydrin. The reaction mixture is stirred at room temperature for 15 hours. The precipitated p- (2,3-epoxy-propoxy)-benzamide, after washing with water and recrystallization from methanol, has a melting point of l44-l46 C.

EXAMPLE 6 Preparation of rac-4'-{3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1 (2H )-pyridyl]-2-hydroxy-propoxy} -aceta.nilide 1.3 g. of 4-(3-chloro-2-hydroxy-propoxy)-acetanilide, 0.9 g. of 4-(p-iluoro-phenyl)-l,2,3,6-tetrahydropyridine, 0.5 g. of sodium bicarbonate and a crystal of potassium iodide are added to a mixture containing ml. of dimethylformamide and 20 ml. of tetrahydrofuran. The resulting mixture is heated at reflux for 24 hours. The reaction mixture, after cooling, is added to water and subsequently extracted with ethyl acetate. After removal of the solvent, the residual rac-4'-{3-[4-(pfluorophenyl )-3 ,6-dihydrol 2H )-pyridyl]-2-hydroxy-propoxy} -acetanilide, upon recrystallization from ethanol, has a melting point of l68l 69 C.

The 4-(3-chloro-2-hydroxy-propoxy)-acetanilide ployed above can be prepared as follows:

4.1 g. of 4'-(2,3-epoxy'propoxy)-acetanilide and 4.6 g. of pyridine hydrochloride are treated with 20 ml. of methanol and heated under reflux conditions for 1 hour. The solvent is evaporated under reduced pressure. The residue is dissolved in n-butanol. The butanol extract is once again washed with water, then dried and evaporated. The residual 4'-(3-chloro- 2-hydroxy-propoxy)-acetanilide, after recrystallization from ethyl acetate, has a melting point of l06-l08 C.

EXAMPLE 7 Preparation of 4'- {3-[4-(p-chloro-phenyl)-3 ,6-dihydro- 1 (2H )-pyridyl]-propoxy }-acetanilide 2.7 g. of 4-(3-bromo-propoxy)-acetanilide, 1.9 g. of 4-(p- 60 chloro-phenyl)-l,2,3,G-tetrahydropyridine, 0.7 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 20 ml. of ethanol for 24 hours. While hot, the mixture is filtered. The crystalline 4'- {3- hydrochloride melts at 260-264 C. after recrystallization 70 from methanol/ethyl acetate.

In an analogous manner there is obtained: By the reaction of 4'-(3-bromo-propoxy)-acetanilide and 4- (p-fluoro-phenyl)- l ,2,3,6-tetrahydropyridine: 4'- {3-[4- acetanilide having a melting point of l72l 73 C. (from methanol);

By the reaction of 4'-(3-bromo-propoxy)-propionanilide and 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine: 4'-{ 3-[4-( p-fluoro-phenyl )-3,6 -dihydro- 1 (2H )-pyridyl propoxy}-propionanilide, having a melting point of l73-l75C. (from methanol);

By the reaction of 4'-( 3 bromo-propoxy)-aceta.nilide and 4- hydroxy-4-(p-fluoro-phenyl)-piperidine: 4-{ 3-[4-(pchloro-phenyl)-4 hydroxy-piperidino]-propoxy} -acetanilide, having a melting point of 229230 C. (from methanol).

EXAMPLE 8 Preparation of rac-4-[{3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2H)-pyridyl]-2-hydroxy-propyl}-thio l-acetanilide hydrochloride 4.5 g. of 4'-(2,3-epoxy-propoxy)-thio-acetanilide and 3.6 g. of 4-(p-fluoro-phenyl)l,2,3,6-tetrahydropyridine are heated under reflux conditions in 30 ml. of ethanol for 1 hour. Approximately two-thirds of the solvent is removed by distillation under reduced pressure. The residual solution is acidified with alcoholic hydrochloric acid and crystallized with ethyl acetate to yield rue-4'-{{3-[4-(p-fluoro-phenyl)-3.6-diydro-l(2H)- pyridyll2-hydroxy-propyl}thi0l-acetanilide hydrochloride which melts at 2 l42l8 C. after recrystallization from methanol/ethyl acetate.

The 4-[(2,3-epoxy-propyl)-thi0]-acetanilide above can be prepared as follows:

33.4 g. of p-acetaminothiophenol are introduced into a solution containing 8.8 g. of sodium hydroxide in 200 ml. of water and treated with 27.6 g. of epichlorohydrin with stirring. The reaction proceeds exotherrnically and is controlled by cooling. The reaction mixture is stirred at room temperature for 12 hours. The 4-(2,3-epoxy-propyl)-thio-acetanilide which precipitates is washed with water and recrystallized from ethyl acetate/cyclohexane and melts at 82 C.

employed EXAMPLE 9 Preparation of rac-p-[{3[4-(p-fluoro-phenyl)-3,6-dihydro-l (2H)-Pyridyl]-2hydroxy-propyl}-thio-chlorobenzene 4.3 g. of 1-[(p chloro-phenyl)-thio]-2,3-epoxy-propane and 3.8 g. of 4-(p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine are heated under reflux conditions in 30 ml. of ethanol for 3 hours. The crystalline rac-p-[{3-[4-(p-fluoro-phenyl)-3,6- dihydro- 1 (2H )-2-pyridyll-2-hydroxy-propyl}-thiolchlorobenzene which precipitates on cooling is recrystallized from methanol and converted to the hydrochloride by addition of alcoholic hydrochloric acid. The hydrochloride salt has a melting point of l78-l 79 C.

In an analogous manner there is obtained:

By the reaction of l-(p-tolyl-thio)-2,3-epoxy-propane and 4-(pfluoro-phenyl)-l,2,3,6-tetrahydropyridine: rac-p- 3-[4-( p-fluoro-phenyl)-3 ,6-dihydrol 2H)-pyridyl]-2- hydroxy-propyl}-thio}-toluene hydrochloride having a melting pointof l74l75 C. (from ethanol);

By the reaction of l-[(p-methoxy-phenyD-thio]-2,3-epoxypropane and 4-(p-fluoro-phenyl)-l ,2,3 ,6- tetrahydropyridine: rac-p-{ 3-[4-(p-fluoro-phenyl)-3,6- dihydrol (2H)-pyridyl -2-hydroxy-propyl }-thio-anisole.

EXAMPLE 10 Preparation of 4'-[{3-[4-(p-fluoro-phenyD-3,6-dihydro-l (2H)-pyridyl]-propyl}-thio]-acetanilide 11.7 g. of 4'-[(3-bromo-propyl)-thio]-acetanilide, 5.4 g. of 4-(p-fluoro-phenyl)- l ,2,3,6-tetrahydropyridine: rac-p-[{ sium carbonate, 0.1 g. of potassium iodide are heated under reflux conditions in 95 ml. of ethanol and 5 ml. of water for 24 hours. The reaction mixture is filtered hot. The 4- [{3-[4-(pfluoro pheny|)-3,o-dihydrol (2H)-pyridyl]-propyl}-thio]- acetanilide which separates out upon cooling melts at l-16 6 C. after recrystallization from methanol.

The 4'-[(3-bromo-propyl)-thio]-acetani1ide above can be prepared as follows:

16.7 g. of 4-acetamino-thiophenol, 60 ml. of ethanol, 8 g. of 50 percent aqueous caustic soda and 156 g. of 1,3-dibromopropane are heated under reflux conditions for 3 hours. The excess 1,3-dibromo-propane is removed by steam distillation. The oil which separates out is taken up in chloroform. The resulting organic phase is washed neutral twice with 1N caustic soda and with water. The oily 4'-[(3-bromo-propyl)- thio]-acetanilide which remains after evaporation of the solvent under reduced pressure is chromatographed on a column of neutral aluminum oxide (activity grade 1) with benzene as the eluting agent. After recrystallization from dilute ethanol, 4'-[(3-bromo-propyl)-thio]-acetanilide melts at 85 C.

In an analogous manner there is obtained:

By the reaction of 4'-[(3-bromo-propoxy)-thio]-acetanilide and 4-11ydroxy-4-(p-chloro-phenyl)-piperidine: 4'-[{3-|4 employed acetanilide having a melting point of 205-206 C. (from methanol).

EXAMPLE 1 1 Preparation of rac-2-{3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1 2H )-pyridyl -2-hydroxy-propoxy}-propionanilide hydrochloride 0.8 g. of o-hydroxy-propionanilide are introduced to a solution containing 120 mg. of sodium in 20 ml. of methanol and thereafter 1.3 g. of 4-(p-fluoro-phenyl)-l-(3-chloro-2-hydroxy-propyl)-l,2,3,6-tetrahydropyridine are added. The mixture is heated under reflux conditions for 24 hours, filtered and the solvent evaporated under reduced pressure. The residue is dissolved in ethyl acetate and converted to the hydrochloride by the addition of alcoholic hydrochloric acid up to the congoacidic reaction. The rac-2'-(3-[4-(p-fluoro-pheny1)-3,6- dihydro-1(2H)-pyridyl]-2-hydroxy-propoxy}-propionanilide hydrochloride which forms melts at 187188 C. after recrystallization from ethanol/ethyl acetate.

The 4-p-fluoro-phenyll 3-chloro-2-hydroxy-propyl)- 1,2,3,6-tetrahydropyridine employed above can be prepared as follows:

7.6 g. of 4-p-fluoro-phenyl-1,2,3,6tetrahydropyridine, 2 drops of piperidine and 40 ml. of absolute ether are cooled to C. and treated over a period of 30 minutes with 3.7 g. of epichlorohydrin in 10 ml. of absolute ethyl ether. The mixture is left to stand at room temperature for 24 hours and at about 0 C. for 60 hours. Thereafter, the solution is filtered and evaporated under reduced pressure. The residual oil is taken up in benzene and chromatographed on a column of Kieselgel with benzene/ether 4:1 as eluting agent. The 4-(p-fluoropheny1)-l-(3-chloro-2-hydroxy-propyl)-1,2,3,6- tetrahydropyridine obtained from the eluate on evaporation, after recrystallization from diethyl ether/petroleum ether, has a melting point of 8385 C.

EXAMPLE 12 Preparation of rac-p-{3-[4-(p-fluoro-phenyl)-3,6-dihydro-1( 2H)-pyridyl1-2-hydroxy-propoxy}-aniline 0.75 g. of rac-p-{3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1( 2H)-pyridyl]-2-hydroxy-propoxy}-nitrobenzene are added to 50 ml. of ethanol. The suspension is heated to 50 C. and, after the addition of 0.5 g. of hydrazine hydrate, is treated portionwise with 0.1 g. of ethanol moistened palladium on carbon percent). The mixture, after the uptake of the required hydrogen is heated under reflux conditions for 1 hour and subsequently filtered. The hot filtrate is concentrated under reduced pressure to begin the crystallization. The precipitated rac-p-{3-[4(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl]-2- hydroxy-propoxy }-aniline, after recrystallization from ethanol, has a melting point of 146-147 C.

The rac-p- {3-[4-( p-fluoro-phenyl )-3 ,6-dihydrol 2H pyridyl]-2-hydroxy-propoxy} -nitrobenzene, employed above, can be prepared in an analogous manner to that described in Example 1, from p-(2,3-epoxy-propoxy)-nitrobenzene and 4- (p-fluoro-phenyl)-l,2,3,6-tetrahydropyridine. The compound, after recrystallization from methanol, has a melting point of l44-145 C.

EXAMPLE 13 Preparation of rac4- {3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1 2H)-pyridyl]-2-hydroxy-propoxy} -aniline dihydrochloride 3.85 g. of rac-4'-{3-[4-(p-fluoro-pheny1)-3,6-dihydrol 2H)-pyridy1]-2-hydroxy-propoxy}-acetani1ide hydrochloride and 20 ml. of about 20 percent hydrochloric acid are heated under reflux conditions for 2 hours. The resulting solution is evaporated under reduced pressure. The residual rac-4'- {3-[ 4-(p-fluoro-phenyl )-3,6-dihydro- 1 (2H pyn'dyl]-2-hydroxy-propoxy}-aniline dihydrochloride melts at 238242 C. (dec.) after two recrystallizations from dioxane/ethyl acetate.

In an analogous manner there is obtained:

By the reaction of rac-2'-{3-[4-(p-fluoro-pheny1)-3,6- dihydro-1(2H)-pyridy1]-2-hydroxy-propoxy}-N-methy1- acetanilide hydrochloride: rac-2'- {3-[4-(p-fluoro-pheny1)-3,6-dihydrol (2H)-pyridyl]-2-hydroxy-propoxy}-N- methylaniline dihydrochloride having a melting point of 262264 C. (from methanol);

By the reaction of 4'-{3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2H)-pyridyl]-propoxy}-acetanilide: 4'-{ 3-[4-(p-fluoropheny1)-3,6-dihydrol (2H)-pyridyl -propoxy }-aniline hydrochloride, the free base of which melts at 102104 C. (from methanol);

By the reaction of rac-4-[{3-[4-(p-fluoro-phenyD-3,6-

dihydro-1(2H)-Pyridyl]-2-hydroxy-propy1}-thiolacetanilide hydrochloride: rac-4'[{3-[4-(p-fluoro-phenyl)-3,6 dihydro 1(2H) pyridyll g-hydroxy-propyl}-thio]- aniline dihydrochloride, the free base of which melts at l40l42 C. (from benzene/cyclohexane);

By the reaction of 4'[{3-{4-(p-fluoro-phenyD-3,6-dihydro- 1(2H)-pyridyl]-propy1}thio]-acetani1ide: 4'-[{3-[4-(pfluoro-pheny1)-3,6-dihydro-l(2H)-pyridyl]-propy1}-thio] -aniline dihydrochloride having a melting point of 228-23 1 C. (from methanol/ethyl acetate).

EXAMPLE 14 Preparation of rac-4-{3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1 (2H)-pyridy1]-2-hydroxy-propoxy}-methanesulfonani1ide 1.8 g. of rac-4'- {3-[4-(p-fluoro-phenyl)-3,6-dihydro-l(21-1)- pyridyl]-2-hydroxy-propoxy}-aniline are dissolved in a mixture comprising 10ml. of absolute benzene, 10 ml. of chloroform and 5 ml. of absolute pyridine with mild heating and treated dropwise with stirring at 05 C. with a solution containing methane-sulfonic acid chloride in 2 ml. of absolute benzene. The reaction mixture is left to stand at room temperature for 16 hours and thereupon, after the addition of 20 ml. of chloroform, poured into water. The oily rac-4'- {3-[4- (p-fluoro-pheny1-3,6-dihydro-1(2H)-pyridyl]-2-hydroxypropoxy}-methanesulfonanilide obtained from the organic phase can be crystallized by trituration with dilute methanol. The rac-4-{ 3-[4-(p-fluoro-phenyl)-3,6-dihydro-l (2H pyridyl]-2-hydroxy-propoxy}-methane-sulfonani1ide melts at 17 1 C. after recrystallization from dilute methanol.

In an analogous manner there is obtained:

By the reaction of rac-4- {3-[4-(p-fluoro-pheny1)-3,6-

dihydro-I(2H)-pyridy1]-2-hydroxy-propyl}-thio]-aniline: rac-4-[{3-[4-(p-fluoro-pheny1)- 3.6-dihydro-1(2H)- pyridyl1-2-hydroxypropyl}thio}-methanesulfonanilide. which has a melting point of 152 C. (from dilute methanol);

By the reaction of 4-(p-fluoro-phenyl)-l-[3-(p-aminophenoxy)-propyl]-1,2,3,6-tetrahydropyridine: 4-{3-[4- (pfluoro-phenyl)-3 ,6-dihydro- 1 (21-1 )-pyridyl ]-propoxy} methanesulfonanilide having a melting point of 147-l48 C. (from methanol);

By the reaction of 4-(p-fluoro-phenyl)-l-{3-[(l-aminophenyl)-thio]-propy}-l ,2,3,o-tetrahydropyridine: 4'-[{3- [4-( p-fluoro-phenyl )-3 ,6-dihydrol (2H)-pyridyl]-propyl} -thiol-methane-sulfonanilide having a melting point of l 39-l 41 C. (from methanol/water).

EXAMPLE 15 Preparation of rac-4-{3'[4-(p-fluoro-phenyl)-3,6-dihydrol 2H )pyridyl]-2-hydroxy-propoxy}-acetanilide 1.7 g. of rac-p-{3-[4-(p-fiuoro-phenyl)-3,6-dihydro-l(2H)- pyridyl]-hydroxy-propoxy}-aniline are dissolved in 20 ml. of 3N acetic acid solution. The solution is treated with l g. of acetic anhydride and after standing at room temperature for 12 hours, evaporated under reduced pressure. The residue is dissolved in chloroform. The chloroform extract is again washed with lN sodium hydroxide solution, dried and evaporated. The residual rac-4-{3-[4-(p-fluoro-phenyl)-3,6- dihydro- 1 (2H)-pyridyl ]-2 hydroxy-propoxy}-acetanilide, after recrystallization from ethanol, melts at 168 C.

EXAMPLE 16 Preparation of rac-4-{ 3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1(2l-l )-pyridyl ]-2-acetoxy-propoxy}-acetanilide hydrochloride pyridyl]-2-hydroxy-propoxy}-acetanilide are dissolved in 21 ml. of dimethylsulfoxide, treated with 14 ml. of acetic anhydride and allowed to stand at room temperature for 20 hours. The solution is poured onto water, whereby the product separates out. The product is converted to the hydrochloride by dissolving it in ethyl acetate and adding alcoholic hydrochloric acid up to congo-acidic reaction. The rac-4-{3- [4-( p-fluoro-phenyl)-3 ,o-dihydrol 2H )-pyridy1]-2-acetoxypropoxy}-acetanilide hydrochloride which is formed melts at 222-230 C. after recrystallization from methanol/ether.

In an analogous manner there is obtained:

By the reaction of 'rac-4'- {3-[4-(p-fluoro-phenyl)-3,6- dihydro- 1 (2H )-pyridyl l-2-hydroxy-propoxy }-propionanilide: rac-4'-{ 3-[4-(p-fluoro-phenyl)-3 ,6-dihydrol (2H pyridyl ]-2-acetoxy-propoxy }-propionanilide hydrochloride.

EXAMPLE 1 7 Preparation of rac-4'- {3-[4-(p-fluoro-phenyl)-piperidino]-2- hydroxy-propoxy}-propionanilide hydrochloride A solution containing 3.8 g. of rac-4-{3-[4-(p-fluoro-phenyl )-3 ,o-dihydrol 2H )-pyridyl]-2-hydroxy-propoxy propionanilide hydrochloride in 250 ml. of 95 percent alcohol and 20 ml. of water are treated with 100 mg. of platinum oxide and hydrogenated at room temperature. The hydrogenation is discontinued upon the uptake of 1 molecular equivalent of hydrogen. The catalyst is removed by filtration, and the solution is evaporated under reduced pressure. The residual rac- 4 {3-[ 4-( p-fluoro-phenyl )-piperidono ]-2-hydroxy-propoxy}- propionanilide hydrochloride, after recrystallization from methanol/ethyl acetate, has a melting point of 207-2 10 C.

EXAMPLE 18 Preparation of rac-4'-{3-[4-(p-tluoro-phenyl)-3,6-dihydro- 1(2l-l )-pyridyl]-2-acetoxy-propoxy}-acetanilide hydrochloride 1.7 g. of racp-{3-[4-(p-fluoro-phenyl)-3,o-dihydro-l(2H)- pyridyl]-2-hydroxy-propoxy}-aniline are dissolved in 10 ml. of dimethylsulfoxide, treated with 7.5 ml. of acetic anhydride and allowed to stand at room temperature for 20 hours. The reaction mixture is thereafter added to water whereby the product precipitates. This is then dissolved in ethyl acetate and converted to its hydrochloride by the addition of alcoholic hydrochloric acid to a Congo-acidic reaction point. The rac- 4'- {34 4-( p-l'luoro-phenyl)-3 o-dihydrol(2H)-pyridyl ]-2 ncctoxypropoxy t-ucctnnilidc hydrochloride, after recrystallization from methanol/ether, has a melting point of 225230 C.

EXAMPLE l9 Preparation of 4'-{3-[4-(p-fluoro-phenyl)-3,6-dihydro- 1(2H)-pyridy1]-2-hydroxy-propoxy} -isobutyranilide hydrochloride and 4'-{3-[4-(p-fluoro-phenyl)-3,6- dihydrol 2H)-pyridyl]-2-hydroxy-propoxy}-isobutyranilide hydrochloride 1.03 g. of rac-4'- {3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2H)-pyridyl1-2-hydroxy-propoxy}-isobutyranilide and 0.45 g. of 0,0-dibenzoyltartrate are dissolved in ml. of hot methanol. The solution is treated at boiling with 0.5 ml. of water and thereafter filtered. Upon cooling, the 4'-{3-[4- (p-fluoro-phenyl )-3,6-dihydro- 1 (2H )-pyridyl]-2-hydroxypropoxy }-isobutyranilide semi-dibenzoyltartrate is precipitated in the crystalline. The rotating salt remains in solution and can be isolated therefrom. The rotating salt, after recrystallization from 10 ml. of methanol, has a melting point of l64l65 C., [a1ig.,=+31.0 (in dimethylsulfoxide, C 1). The rotating salt is shaken with 10 ml. of sodium hydroxide and 10 ml. of chloroform. The base resulting from the organic phase, after recrystallization from ethanol, has a melting point of l83-l84 C., i =+2.2 (in ethanol, C 1). To prepare the hydrochloride, the base is suspended in 5 ml. of ethanol and treated with alcoholic hydrochloric acid until a congo-acidic reaction, whereby all of the material is dissolvedflhe 4'{3-[4-(p-fluoro-phenyl)-3,6-dihydrol(2l-l)-pyridyl]-2 -hydroxy-propoxy} -isobutyranilide hydrochloride has a melting point of 186 C., [04128 l 2. 1 (in ethanol, c =1).

The rotating hydrochloride can be prepared in a like manner by the reaction of rac-4'-{3-[4-(p-fluoro-phenyl)-3 ,6 dihydro- 1 (2H )-pyridyl ]-2-hydroxy-propoxy} -isobutyranilide with 0,0-dibenzoyltartrate.

EXAMPLE Tablets are prepared of the following composition:

Per Tablet -rac-2-{3-[4-(p.fluoro phenyl)-3,6-

dihydro-l (2H )-pyridyl]-2-hydroxypropoxy}-propionanilide hydro-. chloride Lactose Corn starch Talcum Magnesium stearate I0 mg. 63 mg. 74 mg.

2.7 mg. 0.3 mg. Total: 150 mg.

The rac-2'- {3-[4-(p-fluoro-phenyl)-3 ,o-dihydro- 1 (2H pyridyl]-2-hydroxy-propoxy}-propionanilide hydrochloride is mixed with the lactose and the corn starch and granulated with the aid of ethanol. The granulate is dried, mixed with talcum and pressed into tablets.

Individual weight of one tablet Active substance content of one tablet 150 mg. 10 mg.

We claim:

1. A compound of the formula 75 kanoylamido, or lower alkylsulfonylamido; R is hydrogen, halogen, lower alkyl or lower alkoxy; R is halogen; R,, taken together with R is a carbon to carbon bond; X is oxy; and Y is methylene, hydroxymethylene, lower alkanoyloxymethylene or carbonyl, its enantiomers, when Y is hydroxymethylene or alkanoyloxymethylene, or phannaceutically acceptable acid addition salts thereof.

2. A- compound in accordance with claim 1, wherein Y is hydroxymethylene.

3. A compound in accordance with claim 2, wherein R, is lower alkanoylamido; R is hydrogen and R is halogen.

4. A compound in accordance with claim 3, wherein R, is ppropionamido, R is p-fluoro, i.e., rac.-4'- {3-[4-(p-fluorophenyl )-3 ,6-dihydrol 2H )-pyridyl ]-2-hydroxy-propoxy}- propionanilide.

5. A compound in accordance with claim 3, wherein R, is pacetamido; R is p-fluoro, i.e., rac.-4'-{3-[4-(p-fluoro-phenyl )-3 ,o-dihydro-l (2H )-pyridyl ]-2-hydroxy-propoxy} -acetanilide.

6. A compound in accordance with claim 3, wherein R, is pisobutyramido; R is p-fluoro, i.e., rac,-4'- {3-[4-(p-fluorophenyl)-3 ,6-dihydrol 2H )-pyridy1 ]-2-hydroxy-propoxy} isobutyranilide.

7. A compound in accordance with claim 6, (-)-4' {3-[4-(pfluoro-phenyl )-3 ,6-dihydro- 1 (2H )-pyridyl ]-2-hydroxypropoxy}-isobutyranilide.

8. A compound in accordance with claim 6, (+)-4'{ 3-[4-(pfluoro-phenyl)-3 ,6-dihydrol (2H)-pyridyl ]-2-hydroxypropoxy}-isobutyranilide.

9. A compound in accordance with claim 1, wherein Y is methylene.

10. A compound in accordance with claim 9, wherein R, is lower alkanoylamido; R is hydrogen; and R is halogen.

11. A compound in accordance with claim 10, rac. 4-{3-[4- p-chloro-phenyl )-3 ,6-dihydrol 2H )-pyridyl ]-propoxy} acetanilide.

12. A compound in accordance with claim 1, rac.2{3-[4- p-chloro-phenyl )-3,6-dihydrol 2H )-pyridyl ]-2-hydroxy-} propoxy acetanilide.

13. A compound in accordance with claim 1, rac.-2- {3-[4- p-fluoro-phenyl )-3 ,6-dihydrol (2H)-pyridyl ]-2-hydroxy-} propoxy acetanilide.

14. A compound in accordance with claim 1, rac.-p-{3-[4- (p-fluoro-phenyl )-3,6-dihydro l 2H)-pyridyl ]-2-hydroxypropoxy}-ani1ine.

15. A compound in accordance with claim 1, rac.-4- {3-[4- (p-fluoro-phenyl)-3 ,6-dihydro- 1 (2H )-pyridyl]-2-hydroxy-} propoxy methanesulfonanilide.

UNITED STATES PATENT OFFICE 4 CERTIFICATE OF CORRECTION Patent No. 3,675,799 Dated July 4, 1Q72 Inventor(s) Albert Edenhofer and Hans Spiegelberg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 12 Column 16, lines 15 and 1% "-Q-hydroxy- )propoxy" should be: -2-hvdroxy-propox l Claim 15, 001mm 16, lines 16 and 17 "-2-h drQX -I rQ QX should be: -Q-hydroxy-propoxy] Claim 15, Column 16, lines 22 and 23, "-2-hydroxy- }propox y" should be: -2-Qydroxy-propoxyl Signed and sealed this 6th day of March 1973.

(SEAL) Attest:

EDWARD M.PLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM PO-IOSO (10-69) V UBCQMM-DC 5 3375-pgg i us. eovnmnlm unmm; OFFICE I"! o-au-Ju 

2. A compound in accordance with claim 1, wherein Y is hydroxymethylene.
 3. A compound in accordance with claim 2, wherein R1 is lower alkanoylamido; R2 is hydrogen and R3 is halogen.
 4. A compound in accordance with claim 3, wherein R1 is p-propionamido, R3 is p-fluoro, i.e., rac.-4''-(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy -propoxy)-propionanilide.
 5. A compound in accordance with claim 3, wherein R1 is p-acetamido; R3 is p-fluoro, i.e., rac.-4''-( 3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy) -acetanilide.
 6. A compound in accordance with claim 3, wherein R1 is p-isobutyramido; R3 is p-fluoro, i.e., rac.-4''-)3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy -propoxy)-isobutyranilide.
 7. A compound in accordance with claim 6, (-)-4''(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy) -isobutyranilide.
 8. A compound in accordance with claim 6, (+)-4''(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy) -isobutyranilide.
 9. A compound in accordance with claim 1, wherein Y is methylene.
 10. A compound in accordance with claim 9, wherein R1 is lower alkanoylamido; R2 is hydrogen; and R3 is halogen.
 11. A compound in accordance with claim 10, rac. 4''-(3-(4-(p-chloro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-propoxy)acetanilide.
 12. A compound in accordance with claim 1, rac.2''(3-(4-(p-chloro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy -propoxy)acetanilide.
 13. A compound in accordance with claim 1, rac.-2''-(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy -propoxy)acetanilide.
 14. A compound in accordance with claim 1, rac.-p-(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy-propoxy)-aniline.
 15. A compound in accordance with claim 1, rac.-4''-(3-(4-(p-fluoro-phenyl)-3,6-dihydro-1(2H)-pyridyl)-2-hydroxy -propoxy)methanesulfonanilide. 